Meso-ionic didehydro 3a,4,9,10-tetrahydro-1h,3h-(1,2,3)oxadiazolo(3&#39;,4&#39;:1,6)pyrido(3,4-b) indol-3-ones



United States Patent 3,524,859 MESO-IONIC DIDEHYDRO 3a,4,9,10-TETRAHYDRO- 1H,3H-[1,2,3]0XADIAZOLO[3,4':1,6]PYRIDO[3,4-b] INDOL-S-ONES Hans A. Wagner, Skokie, Ill., assignor to G. D. Searle & Co., Chicago, 11]., a corporation of Delaware No Drawing. Continuation-impart of application Ser. No. 687,480, Dec. 4, 1967. This application May 7, 1969, Ser. No. 822,699

Int. Cl. C07d 31/40 US. Cl. 260295 9 Claims ABSTRACT OF THE DISCLOSURE Preparation of 1,2,3,4-tetrahydro-2-nitroso-9H-pyrido [3,4-b]indole-carboxylic acid and the meso-ionic didehydro 3a,4,9,10 tetrahydro 1H,3H-[l,2,3]oxadiazolo[3', 4:1,6]pyrido[3,4-b]indole-3-one intermediates to pepsininhibiting and anti-ulcerogenic 9,10-dihydro-4H-pyrazolo [1,5':1,6]pyrido[3,4-b]indole-2,3-dicarboxylic acids and esters are disclosed.

compounds of the formulas N-N 0 w-o OOH and l lQt,

wherein Z represents an alkyl, cycloalkyl, cycloalkenyl, aralkyl, or optionally-substituted phenyl radical.

Among the alkyl radicals represented by Z, lower alkyl radicals are preferred, i.e., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, isohexyl, heptyl, or like monovalent, saturated, acyclic, straight-or branched-chain, hydrocarbon grouping of empirical formula n 2n+1 wherein n represents a positive integer less than 8.

The cycloalkyl radicals represented by Z are typified by cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; and the cycloalkenyl radicals represented thereby are, specifically, those derived from the aforesaid cycloalkyl radicals by elimination of 2 hydrogeus to give rise to an endocyclic double bond. Among the cycloalkyl and cycloalkenyl radicals represented by Z, the cyclohexyl and A A or A cyclohexyli.e., cyclohexenyl--groupings are preferred.

The aralkyl radicals represented by Z are preferably those comprising a methyl grouping substituted by phenyl wherein a second phenyl or a lower alkyl grouping can also be substituted. Illustrative of such radicals are benzyl,

3,524,859 Patented Aug. 18, 1970 ot-isopropylbenzyl, di-

-O-lower alkyl wherein lower alkyl is defined as before. The halogens embraced by Z are most desirably those of atomic number greater than 9 and less than 53i.e., chlorine and bromine. Positioning of the lower alkoxy or halo substituent about the benzene ring is not critical, 0- m, and psubstituted phenyl groupings alike being contemplated.

Inasmuch as there is at least 1 asymmetric carbon atom present in each of the compounds of this invention, the compounds exist both as racemates and the stereochemically homogeneous isomers which compose them. Compounds in which 2 asymmetric carbon atoms are present, such as the products of Example 7 hereinafter, commonly occur as mixtures of racemates separable, as illustrated, by fractional crystallization.

The compounds to which this invention relates are useful not only as intermediates but also are characterized by valuable pharmacological properties. Thus, for example, they are, variously, pepsin-inhibiting, antiulcerogenic, hypocholesterolemic, anti-microbial in respect of bacteria such as Diplococcus pneumoniae, antiinfiarnmatory, and adapted to prevent dicotyledenous seed germination.

Preparation of the instant intermediates and 9,10-dihydro 4H pyrazolo[l',5:1,6]pyrido[3,4-b]indole-2,3- dicarboxylic acids and esters derived therefrom proceeds by contacting an acetic acid suspension of an appropriate l,2,3,4 tetrahydro 9H-pyrido[3,4-b]indole-3-carboxylic acid COOH [Z being defined as above] with cool aqueous sodium nitrite to give the corresponding 2-nitroso compound, which, upon heating with acetic anhydride, affords the corresponding meso-ionic didehydro 3a,4,9,10-tetrahydro- 1H,3H- 1,2,3 oxadiazolo [3,4: 1,6] pyrido [3,4-b] indole [Z being defined as above]. The latter compound is heated with an appropriate dialkyl acetylenedicarboxylate in ethylene glycol diethyl ether [diethyl Cellosolve] to give the corresponding 9,10-dihydro-4H-pyrazolo[1',5':l,6]pyrido[3,4-b]indole 2,3-dicarboxylic acid ester, from which the free acid is obtained by saponification with hot aqueous methanolic potassium carbonate. The following examples describe in detail compounds illustrative of the present invention and methods which have been devised for the preparation thereof. Throughout the examples hereinafter set forth, temperatures are given in degrees centigrade and relative amounts of materials in parts by weight, except as otherwise noted.

EXAMPLE 1 (A) 1,2,3,4-tetrahydro 2 nitroso-9H-pyrido[3,4- b]- indole-S-carboxylic acid To a suspension of 650 parts of l,2,3,4-tetrahydro-9H pyrido[3,4-b]indole-3-carboxylic acid in 4000 parts of acetic acid at is added, during 30 minutes with stirring a solution of 235 parts of sodium nitrite in 400 parts of water. Stirring is continued 15 minutes longer, whereupon the resultant solution is mixed with decolorizing charcoal and filtered through diatomaceous earth. The filtrate is poured into 25,000 parts of ice-cold water, precipitating a yellowish solid which is filtered off, washed with water, and dried in air. The product thus isolated is 1,2,34-tetrahydro-2-nitroso-9H-pyrido[3,4b]- indole-3-carboxylic acid melting at 176-178" with decomposition.

(B) Meso-ionic didehydro 3a,4,9,lO-tetrahydro-1H,3H-

[1,2,3]oxadiazole [3,4': 1,6]pyrido[3,4-b]indol-3-one A suspension of 50 parts of l,2,3,4-tetrahydro-2- nitroso-9H-pyrido[3,4-b]indole-3-carboxylic acid in 210 parts of acetic anhydride is stirred at 60-65" for 1% hours, during which time solution occurs. The solution is allowed to cool to room temperature during 2 hours, resulting in the formation of a crystalline precipitate. The mixture is poured into 2500 parts of water, and stirring is thereupon resumed for 3 hours. Insoluble solids are filtered 01f, washed on the filter with water, dried in air, slurried in hot methanol, re-isolated by filtration, and washed on the filter with a mixture of cold methanol and ether to give meso-ionic didehydro 3a,4,9,10-tetrahydro 1H,3H [l,2,3]oxadiazolo[3,4';1,6]pyrido[3,4-b]- indol-3-one melting at 247-250 with decomposition.

(C) Dimethyl 9,10-dihydro-4H-pyrazolo[1,5:1,6]pyrido- [3,4-b] indole-2,3-dicarboxylate A suspension of 227 parts of meso-ionic didehydro 3a,4, 9,10 tetrahydro 1H,3H [l,2,3]oxadiazolo[3,4:1,6]- pyrido[3,4-b]indol-3-one in a mixture of 155 parts of dimethyl acetylenedicarboxylate with 1500 parts of ethylene glycol diethyl ether is heated at the boiling point under reflux for 2% hours. Canbon dioxide is liberated and solution occurs in process. The solution is allowed to stand at room temperatures overnight, whereupon precip itation occurs. The precipitate, filtered olf and recrystalilized from acetone, affords dimethyl 9,10-dihydro-4 I-I pyrazolo[1,5':1,6]pyrido[3,4 b]indo1e 2,3 dicarboxylate melting at 253-255 The product has the formula it N I ooooHi COOCH| EXAMPLE 2 9,10 dihydro-4H-pyrazolo[1,5': 1,6] pyrido 3,4-b-] indole-2,3-dicarboxylic acid To a suspension of 65 parts of dimethyl 9,10-dihydro- 4H-pyrazolo[1',5:1,6]pyrido[3,4-b]indole 2,3 dicarboxylate in 100 parts of methanol is added a solution of 60 parts of potassium carbonate in 250 parts of water. The resultant mixture is heated at the boiling point under reflux for 4 hours, then poured into 5000 parts of cold water. The solution which eventuates is stirred with decolorizing charcoal and filtered. The pH of the filtrate is adjusted to 4 with dilute hydrochloric acid, inducing precipitation of a crystalline solid which is isolated by filtration, washed with water, dried in air, washed by trituration with hot methanol, and again dried in air to give 9,l0-dihydro-4H-pyrazolo[1,5: 1,6] pyrido [3,4-b] indole-2,3-dicarboxylic acid melting at 250253 with decomposition. The product has the formula -COOH 4 EXAMPLE 3 (A) 1,2,3,4-tetrahydro-l-methyl-2-nitr0so-9H-pyrido [3,4-b]indole-3-carboxylic acid Substitution of 690 parts of l,2,3,4-tetrahydro-lmethyl-9H-pyrido[3,4-b]indole-3-carboxylic acid for the 1,2,3,4 tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylic acid called for in Example 1(A) affords, by the procedure there detailed, 1,2,3,4-tetrahydro-1-methyl-2-nitroso9H- pyrido[3,4-b]indole-3-carboxylic acid melting at approximately 183-l84 with decomposition.

(B) Meso-ionic didehydro 3a,4,9,l0 tetrahydro-10- methyl 1H,3H [l,2,3]oxadiazolo[3,4':1,6]pyrido [3,4-b] indol-3-one Substitution of 53 parts of 1,2,3,4-tetrahydro-l-methyl- 2-nitroso-9H-pyrido[3,4-b]indole-3-carboxylic acid for the l,2,3,4-tetrahydro-2-nitroso-9H-pyrido-[3,4-b]indole- 3-carboxylic acid called for in Example 1(B) affords, by the procedure there detailed, meso-ionic didehydro 3a,4,9,l0-tetrahydro l0 methyl-1H,3H-[l,2,3]oxadiazolo[3,4:1,6]pyrido[3,4-b]indol-3-one. The product decomposes at approximately 250 without melting.

(C) Dimethyl 9,10-dihydro-l0-methyl-4H-pyrazolo [1,5: 1,6] pyrido[3,4-b] indole-2,3-dicarboxylate CH3 N -o 0 0 OH;

EXAMPLE 4 9,IO-dihydro-10-methyl-4H-pyrazolo[1,5: 1,6 pyrido [3,4-b]indole-2,3-dicarboxylic acid Substitution of 68 parts of dimethyl 9,10-dihydro-l0- methyl 4H pyrazolo[1,5':1,6]pyrido[3,4-b]indole- 2,3-dicarboxylate for the dimethyl 9,10-dihydro-4H-pyrazolo[l,5':1,6]pyrido[3,4-b]indole 2,3 dicarboxylate called for in Example 2 affords, by the procedure there detailed, 9,I-O-dihydro-l0-methyl-4H-pyrazolo[1,5: 1,6] pyrido[3,4-b]indole-2,3-dicarboxylic acid melting at approximately 275-276. The product has the formula CH: H /N To OOH i oooH EXAMPLE 5 (A) l-cyclohexyl-l,2,3,4-tetrahydro-9H-pyrido [3,4-b] indole-3-car'boxylic acid To a solution of -8=l7 parts of L-tryptophan in a mixture of parts of 96% sulfuric acid and 5000 parts of water is added a solution of 493 parts of cyclohexanecarboxaldehyde in 5000 parts of ethanol. The resultant solution is heated at the boiling point under reflux in a nitrogen atmosphere for 17 hours, whereupon 400 parts of concentrated ammonium hydroxide followed by 20 parts of decolorizing charcoal is slowly introduced. Heating at the boiling point under reflux is resumed for 10 minutes, at which point the mixture is filtered hot. The filtrate is diluted with 2000 parts of concentrated ammonium hydroxide and allowed to cool. The crystalline precipitate thrown down is l-cyclohexyl-l,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylic acid which, filtered off, Washed well with water, and dried in air, melts at 202-204.

(B) l-cyclohexyl-1,2,3,4-tetrahydro-2-nitroso-9'H-pyrido- [3,4-b] indole-3-carboxylic acid To a suspension of 463 parts of 1-cyclohexyl-1,2,3,4- tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylic acid in 3000 parts of acetic acid at 15 is added, during 30 minutes with stirring, a solution of 117 parts of sodium nitrite in 300 parts of water. Stirring is continued 15 minutes longer, whereupon the resultant solution is treated with decolorizing charcoal and filtered. The filtrate is poured into 20,000 parts of ice-cold water, precipitating a yellowish solid which is filtered olf, washed with water, and dried in air. The product thus isolated is l-cyclohexyl 1,2,3,4 tetrahydro-Z-nitroso-9H-pyrido[3,4-b]indole-3-carboxylic acid.

(C) Meso-ionic didehydro 10-cyclohexyl-3a,4,9,lO-tetrahydro 1H,3H [1,2,3]oxadiazolo[3',4:1,6]pyrido- [3,4-b]indo1-3-one A solution of 43 parts of 1-cyclohexyl-1,2,3,4-tetrahydro 2 nitroso-9H-pyrido[3,4-b]indole-3-carboxylic acid in 270 parts of acetic anhydride is heated to 50 with stirring, whereupon heating is discontinued while stirring is maintained for 2 hours longer. The resultant mixture is poured into 2000 parts of Water. The mixture thus obtained is stirred for 3 hours, whereupon insoluble solids are filtered off, Washed with water, dried in air, and further washed by slurrying in hot methanol. The resultant product is meso-ionic didehydro 10-cyclohexyl- 3a,4,9,10 tetrahydro-1H,3H-[1,2,3]oxadiazolo[3',4: 1,6] pyrido[3,4-b]indol-3-one melting at 214-2160.

(D) Dimethyl 10-cyclohexyl-9,10-dihydro-4H-pyrazolo- [1,5 1,6]pyrido [3,4-b] indole-2,3-dicarboxylate A suspension of 232 parts of meso-ionic didehydro 10 cyclohexyl 3a,4,9,l0-tetrahydro-1H,3H-[1,2,3]oxadiazolo[3',4:1,6]pyrido[3,4-b]indol-3-one in a mixture of 116 parts of dimethyl acetylenedicarboxylate with 2000 parts of ethylene glycol diethyl ether is heated at the boiling point under reflux for 5 hours. Solvent is removed from the resultant solution by vacuum distillation. The residue is chromatographed on silica gel, using benzene and ethyl acetate as developing solvents. From an eluate comprising 20% ethyl acetate in benzene, on evaporation of solvent, dimethyl lO-cyclohexyl 9,10 dihydro-4H- pyrazolo[l',5:1,6]pyrido[3,4 b] indole-2,3-dicarboxylate is obtained as the residue. The product has the formula oooom EXAMPLE 6 (A) 1-(3-cyclohexenyl)-1,2,3,4-tetrahydro-9H-pyrido- [3,4-b]indole-3-carboxylic acid Substitution of 484 parts of 3-cyclohexene-1-carboxaldehyde for the cyclohexanecarboxaldehyde called for in Example 5 (A) affords, by the procedure there detailed, 1 (3-cyclohexenyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b] indole-3-carboxylic acid melting at 193-195 with decomposition.

6 (B) 1-(3-cyclohexenyl)-1,2,3,4-tetrahydro-2-nitroso-9H pyrido[3,4-b]indole-3-carboxylic acid Substitution of 460 parts of 1-(3-cyclohexenyl)-1,2,3,4- tetrahydro-9H-pyrido[3,4-b]indole 3 carboxylic acid for the l-cyclohexyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b] indole-3-carboxylic acid called for in Example 5 (B) affords, by the procedure there detailed, l-(3-cyclohexenyl)-l,2,3,4-tetrahydro 2 nitroso 9H pyrido- [3,4-b]indole-3-carboxylic acid.

(C) Meso ionic didehydro 1O (3 cyclohexenyl)- 3a,4,9,10 tetrahydro 1H,3H [1,2,3]oxadiazolo- [3,4:1,6]pyrido[3,4-b]indol-3-one Substitution of 43 parts of 1-(3-cyclohexenyl)-l,2,3,4 tetrahydro 2 nitroso 9H pyrido[3,4 b]indole 3- carboxylic acid for the l-cyclohexyl-l,2,3,4-tetrahydro-2- nitroso-9H-pyrido[3,4-b]indole-3-carboxylic acid called for in Example 5 (C) affords, by the procedure there detailed, meso-ionic didehydro l0 (3 cyclohexenyl)- 3a,4,9,l0 tetrahydro 1H,3H [1,2,3]oxadiazolo- [3,4':l,6]pyrido[3,4-b]indol-3-one melting at 216218 with decomposition.

(D) Dimethyl 10-(3-cyclohexenyl)-9,10dihydro 4H- pyrazolo[l',5:1,6]pyrido[3,4 b]indole 2,3 di carboxylate -COOCHa COOOHa EXAMPLE 7 10-(3-cyclohexenyl)-9,10-dihydro-4H-pyrazolo[1,5': 1,6] pyrido [3 ,4-b indole-2,3-dicarboxylic acid A mixture of 81 parts of dimethyl 10-( 3-cyclohexenyl)- 9,10 dihydro 4H pyrazolo[1,5:l,6]pyrido[3,4-b]indole-2,3-dicarboxylate and 60 parts of potassium carbonate with 900 parts of methanol and 300 parts of water is heated at the boiling point under reflux for 2 hours and then stirred into 7500 parts of water. The resultant mixture is let stand at around 5 overnight, at which point insoluble solids are filtered ofi, Washed with ice-cold water, dried in air, and extracted With 20 volumes of boiling methanol. The material which remains insoluble is filtered out, consecutively Washed with methanol and ether, and dried in air. The product thus isolated is 10-(3cyclohexenyl) 9,10-dihydro-4H-pyrazolo[1,5: l,6]pyrido[3,4-b] indole-2,3-dicarboxylic acid melting at 282-284, and having the formula The boiling extract is mixed with decolorizing charcoal, and the mixture is filtered. The filtrate is concentrated by distillation to the point of incipient precipitation, then allowed to cool to room temperature. The precipitate is thereupon filtered oil? and dried in air. The product thus isolated is (3 -cyclohexenyl -9, l 0-dihydro-4H-pyrazolo [1,5':1,6]pyrido[3,4-b]indole-2,3-dicarboxylic acid melting at approximately 265-266".

EXAMPLE 8 (A) 1,2,3,4-tetrahydro-2-nitroso-1-phenyl-9H'pyrido [3,4- b]indole-3-carboxylic acid To a suspension of 450 parts of 1,2,3,4-tetrahydro-lphenyl-9H-pyrido[3,4-b]indole-3-carboxylic acid in 2000 parts of acetic acid at is added, during minutes with stirring, a solution of 127 parts of sodium nitrite in 200 parts of water. The resultant solution is mixed with decolorizing charcoal, the mixture is filtered, and the filtrate is poured into 20,000 parts of ice-cold water. The yellow solid which precipitates is filtered off, washed with cold water, and dried in air. The resultant product is 1,2,3,4-tetrahydro 2 nitroso-l-phenyl-9H-pyrido[3,4-b] ind0le-3-carboxylic acid.

(B) Meso-ionic didehydro 3a,4,9,IO-tetrahydro-lO-phenyl 1H,3H [1,2,3]oxadiazolo[3,4':l,6]pyrido[3,4-b] indol-3-one A solution of parts of 1,2,3,4-tetrahydro-2-nitroso-1- phenyl-9H-pyrido[3,4-b]indole-3-carboxylic acid in 150 parts of acetic anhydride is heated to whereupon heating is discontinued and the solution stirred for 2 hours and then poured into 1700 parts of water. The resultant mixture is stirred for 3 hours, at which point insoluble solids are filtered out, Washed with water, dried in air, and washed by trituration in hot methanol to give mesoionic didehydro 3a,4,9,10-tetrahydro 10 phenyl-1H,3H- [1,2,3]oxadiazolo[3',4':1,6]pyrido[3,4-b]indol 3 one melting at 228-230 with decomposition.

(C) Dimethyl 9,10 dihydro 10 phenyl 4H pyrazolo [1,5':1,6]pyrido[3,4-b]indole-2,3-dicarboxylate A suspension of 12 parts of meso-ionic didehydro 3a,4,9,10 tetrahydro-l0-phenyl-1H,3H-[1,2,3]oxadiazolo [3,4':1,6]pyrido[3,4ab]indol-3-one in a mixture of 10 parts of dimethyl acetylenedicarboxylate with parts of ethylene glycol diethyl ether is heated at the boiling point under reflux for 3 hours, whereupon solvent is removed by vacuum distillation and the residue chromatographed on silica gel. From an eluate comprising 10% ethyl acetate in benzene, on evaporataion of solvent and recrystallization of the residue from a mixture of acetone and n-pentane, dimethyl 9,10-dihydro-10-phenyl-4H-pyrazolo[1,5: l,6]pyrido[3,4-b]indole 2,3 dicarboxylate melting at approximately 225-226" is obtained. The product has the formula COOCHs EXAMPLE 9 (A) 1-(p-chlorophenyl)-1,2,3 ,4-tetrahydro-2-nitroso- 9H-pyrido[3,4-b]indole-3-carboxylic acid Substitution of 490 parts of l-(p-chlorophenyl-l,2,3,4- tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylic acid for the 1,2,3,4-tetrahydro-l-phenyl-9H-pyrido[3,4 b]indole-3- carboxylic acid called for in Example 8(A) affords, by the procedure there detailed, l-(p-chlorophenyl)-1,2,3,4- tetrahydro 2 nitroso-9H-pyrido[3,4-b]indole-3-carboxylic acid.

(B) Meso-ionic didehydro lO-(p-chlorophenyl)-3a,4,9,10-

tetrahydro 1H,3H [1,2,3]oxadiazolo[3',4':1,6]pyrido [3,4-b]indol-3-one Substitution of 39 parts of l-(p-chlorophenyl)-1,2,3,4- tetrahydro-2-nitroso-9H pyridol[3,4-b]indole-3-carboxylic acid for the 1,2,3,4-tetrahydro-2-nitroso-1-phenyl-9H- pyrido[3,4-b]indole-3-carboxylic acid called for in Example 8(B) affords, by the procedure there detailed, meso-ionic didehydro 10-(p-chlorophenyl)-3a,4,9,10-tetrahydro 1H,3H [1,2,3]oxadiazolo[3',4:1,6]pyrido [3,4-b1indol-3-one melting at 224-226 with decomposition.

(C) Dimethyl 10-(p-chlorophenyl)-9,l0-dihydro 4H- pyrazolo[1',5': 1,6]pyrido [3,4-b]indole-2,3-dicarboxylate A suspension of parts of meso-ionic didehydro 10- (p-chlorophenyl)-3a,4,9,10-tetrahydro 1H,3H-[l,2,3] oxadiazolo[3,4':l,6]pyrido[3,4'b]indol-3-one in a mixture of 70 parts of dimethyl acetylenedicarboxylate with 1000 parts of ethylene glycol diethyl ether is heated at the boiling point under reflux for 3 hours, whereupon it is mixed with decolorizing charcoal and filtered. The filtrate is freed of solvent by vacuum distillation; and the residue is chromatographed on silica gel, using benzene and ethyl acetate as developing solvents. From an eluate comprising 10% ethyl acetate in benzene, on evaporation of solvent and recrystallization of the residue from a mixture of acetone and n-hexane, dimethyl 10-(p-chlorophenyl)- 9,10 dihydro 4H-pyrazolo[l,5:1,6]pyrido[3,4-b]indole-2,3-dicarboxylate melting at approximately 233234 is obtained. The product has the formula N I I \COOCH: oooom EXAMPLE 10 (A) l-(m-bromophenyl)-1,2,3,4-tetrahydro-9H-pyrido [3,4-b] indole-3-carboxylic acid Substitution of 814 parts of m-bromobenzaldehyde for the cyclohexanecarboxaldehyde called for in Example 5(A) alfords, by the procedure there detailed, l-(mbromophenyl)-1,2,3,4 tetrahydro 9H pyrido[3,4-b] indole-3-carboxylic acid.

(B) 1- m-bromophenyl)-1,2,3,4-tetrahydro-2-nitroso- 9H-pyrido 3,4-b indole-3 -carboxylic acid Substitution of 572 parts of l-(m-bromophenyl)-l,2,3,4- tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylic acid for the 1,2,3,4-tetrahydro 1-phenyl-9H-pyrido[3,4-b]indole- 3-carboxylic acid called for in Example 8(A) alfords, by the procedure there detailed, 1(m-bromophenyl)-1,2,3,4- tetrahydro-Z-nitroso 9H pyrido[3,4-b]indole-3-carboxylic acid.

(C) Meso-ionic didehydro IO-(m-bromophenyl)-3,4,9,10-

tetrahydro 1H,3H [l,2,3]oxadiazo[3,4':1,6]pyrido [3,4-b]indol-3-one 9 (D) Dimethyl 10-(m-bromophenyl)-9,10 dihydro-4H- pyrazolo[1',5: 1,6]pyrido [3 ,4-b] indole-2,3-dicarboxylate Substitution of 15 parts of meso-ionic didehydro 10- (m-bromophenyl) 3a,4,9,10 tetrahydro-1H,3H-[1,2,3] oxadiazolo[3',4':1,6]pyrido[3,4b]indol-S-one for the meso-ionic didehydro 321,4,9,IO-tetrahydro-lO-phenyb 1H,3H [1,2,3]oxadiazolo[3,4':1,6]pyrido[3,4-b]indol- 3-one called for in Example 8(C) affords, by the procedure there detailed, dimethyl 10-(rn-bromophenyl)- 9,10-dihydro 4H pyrazo1o[1',5:1,6]pyrido[3,4-b]indole-2,3-dicarboxylate, having the formula H /N ooocrn EXAMPLE 11 (A) 1,2,3,4-tetrahydro-l-(p-methoxyphenyl)-2-nitroso- 9H-pyrido 3 ,4-b] indole-3-carboxylic acid Substitution of 480 parts of 1,2,3,4-tetrahydro-1-(prnethoxyphenyl) 9H pyrido[3,4-b]indole-3-carboxy1ic acid for the l,2,3,4-tetrahydro-1-phenyl-9H-pyrido[3,4-b] indole-3-carboxylic acid called for in Example 8(A) affords, by the procedure there detailed, 1,2,3,4-tetrahydrol-(p methoxyphenyl) 2 nitroso9H-pyrido[3,4-b] indole-3-carboxylic acid.

(B) Meso-ionic didehydro 3a,4,9,IO-tetrahydro-lO-(pmethoxyphenyl) 1H,3H [1,2,3]oxadiazolo[3,4:1,6] pyrido[3,4-b1indol-3-one Substitution of 13 parts of meso-ionic didehydro 3a,4, 9,10 tetrahydro 10 (pmethoxyphenyl) 1H,3H [1, 2,3]oxadiazolo[3',4:1,6]pyrido[3,4 b]indo1 3 one for the mesoionic didehydro 3a,4,9,10 tetrahydro 10- phenyl 1H,3H [1,2,3]oxadiazolo[3,4:1,6]pyrido[3, 4-b]indo1 3 one called for in Example 8(0) aitords, by the procedure there detailed, dimethyl 9,10 dihydro- 10 (p-methoxyphenyl) 4H pyrazolo[1',5:1,6]pyrido [3,4-b]indole 2,3 dicarboxylate. The product has the formula it N cocHa -COOCHa EXAMPLE 12 (A) 1-(o-ethoxyphenyl)-1,2,3,4-tetrahydro-9H- pyrido 3,4-b] indo1e-3-carboxylic acid Substitution of 660 parts of o-ethoxybenzaldehyde for the cyclohexanecarboxaldehyde called for in Example 10 5(A) affords, by the procedure there detailed, l-(oethoxyphenyl) 1,2,3,4 tetrahydro 9H pyrido[3,4- b]indole-3-carboxylic acid.

(B) 1-(o-ethoxyphenyl)-1,2,3 ,4-tetrahydro-2-nitroso- 9H-pyrido [3 ,4-b] indole-3-carboxylic acid Substitution of 518 parts of l-(o-ethoxyphenyl)-1,2,3, 4 tetrahydro 9H pyrido[3,4-b1indole 3 carboxylic acid for the 1,2,3,4 tetrahydro-1-phenyl-9H-pyrido[3, 4-b]indole-3-carboxylic acid called for in Example 8(A) affords, by the procedure there detailed, l-(o-ethoxyphenyl) 1,2,3,4 tetrahydro 2 nitroso 9H pyrido[3, 4-b] indole-3-carboxy1ic acid.

(C) Meso-ionic didehydro IO-(o-ethoxyphenyl)-3a,4,9, 10 tetrahydro 1H,3H [1,2,3]oxadiazolo[3',4':1, 6] pyrido- 3,4-b] indol-3-one Substitution of 40 parts of l-(o-ethoxyphenyl)-1,2,3,4- tetrahydro 2 nitroso 9H pyrido[3,4-b1indole 3- carboxylic acid for the 1,2,3,4 tetrahydro 2 nitroso- 1 phenyl 9H pyrido[3,4-b1indole 3 carboxylic acid called for in Example 8(B) affords, by the procedure there detailed, meso-ionic didehydro 10-(o-ethoxyphenyl)- 3a,4,9,10 tetrahydro 1H,3H [1,2,3]oxadiazolo[3', 4': 1,6] pyrido[3,4-b1indol-3-one.

(D) Dimethyl 10 (o-ethoxyphenyl)-9,10-dihydro-4H- pyrazolo[1',5':1,6]pyrido[3,4 b]indole 2,3 dicarboxylate Substitution of 15 parts of meso-ionic didehydro 10-(0- ethoxyphenyl) 3a,4,9,10 tetrahydro 1H,3H [1,2, 3]0xadiazolo[3',4':1,6]pyrido[3,4 b]indol 3 one for the meso-ionic didehydro 3a,4,9,lO-tetrahydro-lO-phenyl- 1H,3H [1,2,3]oxadiazolo[3,4:1,6]pyrido[3,4-b]indol- 3-one called for in Example 8(C) affords, by the procedure there detailed, dimethyl IO-(o-ethoxyphenyl)-9,10- dihydro 4H pyrazo1o[1',5:1,6]pyrido[3,4-b1indole-2, 3-dicarboxy1ate. The product has the formula OC2H5 5 N -ooootn EXAMPLE 13 (A) 1-benzyl-1,2,3,4-tetrahydro-2-nitroso-9H- pyrido[3,4-b] indole-3-carboxylic acid To a suspension of 67 parts of 1-benzyl-1,2,3,4-tetrahydro 9H pyrido[3,4-b]indole-3-carboxylic acid in 400 parts of acetic acid at 15 is added, during 30 minutes with stirring, a solution of 17 parts of sodium nitrite in 35 parts of water. The resultant solution is mixed with decolorizing charcoal, the mixture is filtered through diatomaceous earth, and the filtrate is stirred into 3000 parts of water. The yellow solid which precipitates is filtered oflf, washed with water, and dried in air. The product thus isolated is l-benzyl 1,2,3,4 tetrahydro-2- nitroso-9H-pyrido[3 ,4-b indole-3-carboxylic acid.

(B) Meso-ionic didehydro 10 benzyl 3a,4,9,10 tetrahydro 1H,3H [1,2,3]0xadiazolo[3,4:1,6]pyrido[3, 4-b]indole-3-one A solution of 65 parts of 1-benzyl-1,2,3,4-tetrahydro-2- nitroso-9H-pyrido[3,4-b]indole-3-carboxylic acid in 300 parts of acetic anhydride is heated to 50, whereupon heating is discontinued and the solution is stirred for 2 hours and then poured into 2500 parts of Water. The resultant mixture is stirred for 4 hours, at which point insoluble solids are filtered out, washed with water, dried in air, and recrystallized from methanol to give mesoionic didehydro 10 -benzyl-3a,4,9,10-tetrahydro-1H,3H-

[1,2,3]oxadiazolo[3,4':1,6]pyrido[3,4-b]indol 3 one melting at 215-217".

(C) Dimethyl 10-benzyl-9,10-dihydro-4H-pyrazolo[1', 5': 1,6] pyrido [3 ,4-b] indole-2,3 -dicarboxylate A suspension of 22 parts of meso-ionic didehydro lbenzyl 3a,4,9,10 tetrahydro 1H,3H [1,2,3]oxadiazolo[3',4':1,6]pyrido[3,4-b]indol-3-one in a mixture of 11 parts of dimethyl acetylenedicarboxylate with 200 parts of ethylene glycol diethyl ether is heated at the boiling point under reflux for 8 hours, whereupon solvent is recoved by vacuum distillation and the residue recrystallized from a mixture of acetone and n-pentane to give dimethyl 10 benzyl 9,10 dihydro 4H pyrazolo [1, ':1,6]pyrido[3,4 b]indole 2,3 dicarboxylate melting at approximately 206-207. The product has the formula EXAMPLE 14 -benzyl-9,10-dihydro-4H-pyrazolo[ 1,5 1,6] pyrido [3,4-b]indole-2,3-dicarboxylic acid A mixture of 80 parts of dimethyl 10-benzyl-9,l0-dihydro 4H pyrazolo[1,5':1,6]pyrido[3,4-b]indole-2,3- dicarboxylate with 1000 parts of methanol and a solution of 60 parts of potassium carbonate in 250 parts of water is heated at the boiling point under reflux for 4 hours and then poured into 5000 parts of cold water. The resultant solution is stirred with decolorizing charcoal and then filtered. The pH of the filtrate is adjusted to 4 with dilute hydrochloric acid, precipitating a crystalline solid which, filtered off, Washed with water, dried in air, and recrystallized from methanol, affords 10-benzyl-9,10-dihydro-4H- pyrazolo[1',5:1,6]pyrido[3,4 b]indole 2,3 dicarboxylic acid melting at 226228. The product has the formula EXAMPLE 15 (A) 1,2,3,4-tetrahydro-1-(wmethylbenzy1-2-nitroso-9H- pyrido 3,4-b] indole-3-carboxylic acid To a suspension of 490 parts of 1,2,3,4-tetrahydro-1- (a methylbenzyl 9H pyrido[3,4-b]indole-3-carboxylic acid in 3000 parts of acetic acid at 15 is added, during minutes with stirring, a solution of 115 parts of sodium nitrite in 250 parts of water. The resultant solution is mixed with decolorizing charcoal, the mixture is filtered through diatomaceous earth, and the filtrate is stirred into 3000 parts of water. The yellow solid which precipitates is filtered off, washed with water, and dried in air. The product thus isolated is 1,2,3,4-tetrahydro-l-(a-methylbenzyl) 2 nitroso 9H-pyrido[3,4-b]indole-3-carboxylic acid.

(B) Meso-ionic didehydro 3a,4,9,10 tetrahydro IO-( methylbenzyl) 1 H [1,2,3]0xadiazolo[3',4';1,6] PY ,4-b]ind0l-3-one 12 A solution of 65 parts of 1,2,3,4-tetrahydro-1-(a-methylbenzyl) 2 nitroso-9H-pyrido[3,4-b]indole-3-carboxylic acid in 3000 parts of acetic anhydride is heated to 50, whereupon heating is discontinued and the solution is stirred for 2 hours and then poured into 2500 parts of water. The resultant mixture is stirred for 4 hours, at

which point insoluble solids are filtered out, washed on with 1000 parts of ethylene glycol diethyl ether is heated at the boiling point under reflux for 5 hours, whereupon solvent is removed by vacuum distillation and the residue chnomatographed on silica gel. From an eluate comprising 10% ethyl acetate in benzene, on evaporation of solvent and recrystallization of the residue from a mixture of acetone and n-pentane, dimethyl 9,10-dihydro-10-(oamethylbenzyl) 4H pyrazo1o[1, 5:1,6]pyrido[3,4-b] indole-2,3-dicarboxylate melting at approximately 155- 156 is obtained. The product has the formula N COOCH! -COOCHa EXAMPLE 16 9,10 dihydro 10 (cc methylbenzyl) 4H pyrazolo [1,5': 1,6] pyrido [3,4-b] indole-2,3-dicarboxylic acid Substitution of parts of dimethyl 9,10-dihydro-l0- (a methylbenzzyl) 4H pyrazolo[1',5':1,6]pyrido[3, 4-b]indole-2,3-dicarboxylate for the dimethyl IO-benzyl- 9,10 dihydro 4H pyrazolo[1,5':1,6]pyrido[3,4-b] indole-2,3-dicarboxylate called for in Example 14 affords, by the procedure there detailed, 9,10-dihydro-10-(a-methylbenzyl) 4H pyrazolo[1',5:1,6]pyrido[3,4-b]indole- 2,3-dicarboxylic acid melting at approximately 263264. The product has the formula HJJCH: N

, -o00rr 0011 EXAMPLE 17 (A) 1,2,3,4-tetrahydro-1-diphenylmethyl-9H-pyrido [3,4-b]indole-3-carboxylic acid Substitution of 860 parts of diphenyl acetaldehyde for the cyclohexanecarboxaldehyde called for in Example 5A affords, by the procedure there detailed, 1,2,3,4 tetrahydro 1 diphenylmethyl 9H pyrido[3,4-b]indole-3- carboxylic acid melting at approximately 197198.

13 (B) 1,2,3,4-tetrahydro-2-nitroso-l-diphenylmethyl-9H- pyrido 3,4-b] indole-3-carboxylic acid To a suspension of 50 parts of 1,2,3,4-tetrahydro-l-diphenylmethy1-9H-pyrido'[3,4-b]indole 3 carboxylic acid in 350 parts of acetic acid at 15 is added, during 30 minutes with stirring, a solution of parts of sodium nitrite in 25 parts of water. Stirring is continued 30 minutes longer, whereupon the resultant solution is treated with decolorizing charcoal and filtered. The filtrate is poured into 2000 parts of ice-cold water, precipitating a yellowish solid which is filtered oif, washed with cold water, and dried in air to give 1,2,3,4-tetrahydro-2-nitroso-l diphenylmethyl-9H-pyrido[3,4-b]indole-3-carboxylic acid melting at 189191.

(C) Mesa-ionic didehydro 3a,4,9,10 tetrahydro 10 diphenylmethyl 1H,3H [1,2,3]oxadiazolo[3',4':1,6] pyrido[3,4-b]indol3-one A solution of 50 partsof 1,2,3,4-tetrahydro-2-nitroso-1- diphenylmethyl-9H-pyrido[3,4-b]indole-3-carboxylic acid in 250 parts of acetic anhydride is heated to 55", whereupon precipitation occurs and heating is discontinued. The resultant solution is stirred for 2 hours, then poured into 2000 parts of water. Stirring is resumed for 3 hours, at which point insoluble solids are filtered out, washed with water, dried in air, and recrystallized from methanol to give meso-ionic didehydro 3a,4,9,IO-tetrahydro-lO-diphenylmethyl 1H,3H [1,2,3]oxadiazolo[3',4:1,6]pyrido[3, 4-b]indol-3-one meltingat 243-245 with decomposition.

(D) Dimethyl 9,10-dihydro-10-diphenylmethyl-4H-pyrazolo[1,5: 1,6 pyrido [3,4-b] indole-2,3-dicarboxylate Q Q N,

i-G O O CH:

EXAMPLE 18 9,10-dihydro-10-diphenylmethyl-4H-pyrazolo 1,5 1,6] pyrido[3,4-b] indole-2,3-dicarboxylic acid To a suspension of 97 parts of dimethyl 9,10-dihydro- 10-diphenylmethyl 4H-pyrazolo[1,5': 1,6]pyrido[3,4-b] indole 2,3 dicarboxylate in 1000 parts of methanol is added a solution of 60 parts of potassium carbonate in 250 parts of water. The resultant mixture is heated at the boiling point under reflux for 4 hours, then poured into 5000 parts of cold water. The solution which eventuates is stirred with decolorizing charcoal and filtered. The pH of the filtrate is adjusted to 4 with dilute hydrochloric 13 N l ooon ooon What is claimed is: 1. A compound of the formula wherein R represents hydrogen, lower alkyl, cyclohexyl, cyclohexenyl, phenyl, halophenyl in which the halo constituent is chlorine or bromine, (lower alkoxy)phenyl, benzyl, a-methylbenzyl, or diphenylmethyl.

2. A compound according to claim 1 which is mesoionic didehydro 3a,4,9,l0 tetrahydro 10-methyl-1H,3H- [1,2,3]oxadiazolo[3',4:1,6]pyrido[3,4 b]indol 3 one.

3. A compound according to claim 1 which is mesoionic didehydro 10 (3-cyclohexenyl)-3a,4,9,10-tetrahydro 1H,3H [l,2,3]oxidiazolo[3,4':1,6]pyrido[3,4-b] indol-3-one.

4. A compound according to claim 1 which is mesoionic didehydro 3a,4,9,10 tetrahydro 10-phenyl-1H,3H- [1,2,3]oxadiazo1o[3,4: 1,6] pyrido[3,4-b]indol-3-one.

5. A compound according to claim 1 wherein R represents halophenyl in which the halo constituent is chlorine or bromine.

6. A compound according to claim 1 which is mesoionic didehydro 10 (p-chlorophenyl)-3a4,9,lO-tetrahydro 1H,3I-I [1,2,3]oxadiazolo[3',4:1,6]pyrido[3,4-b] indol-3-one.

7. A compound according to claim 1 which is mesoionic didehydro 10 benzyl 3a,4,9,10-tetrahydro-1H, 3H [1,2,3]oxadiazolo[3',4:l,6]pyrido[3,4 b]indol-3 one.

8. A compound according to claim 1 which is mesoionic didehydro 3a,4, 9,10 tetrahydro-10-(a-methylbenzy1-1H,3H [1,2,3]oxadiazolo[3,4':1,6]pyrido[3,4 b] indol-3-one.

9. A compound according to claim 1 which is mesoionic didehydro 3a,4,9,Ill-tetrahydro-10-diphenylmethyl 1H,3H [1,2,3]oxadiazolo[3',4:1,6]pyrido[3,4 bjindol- 3-one.

References Cited UNITED STATES PATENTS 3,299,078 l/l967 Pachter 260296 HENRY R. JILES, Primary Examiner A. L. ROTM-AN, Assistant Examiner US. Cl. X.R. 424-263 Page 1 of 2 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3, 521', 59 Dated August 1970 Inventor) Hans A. Wagner It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, line 1 "indole-carboxylic" should be --indole5-carboxylic-.

Column 1, line 1 4, "acid and the" should be --acid and--.

Column 1, the second formula,

f 0 0 should be I O C Column 2, line 13, "0-,m, and p-" should be -o-, m-, and

Column 3, line 9, "l,2,3 L-" should be -l,2, 5, 4-

Column 5, line 13, "oxadiazole" should be oxadiazolo-.

Column 5, line 26, "[5' i' ;l,6] should be --[3', l-' :l,6]--.

Column 3, line 52 "100" should be --lOOO--.

Column the first formula N coocH should be N coocH 5 COOCH Page 2 of 2 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3, 59M, 59 Dated August 1970 In n fls) Hans A. Wagner It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column l, line '72, "M00 parts" should be OOO parts-.

Column 8, line 61, "l(m-bromophenyl)-" should be -l-(mbromophenyl)- Column 12, line L7, "(a-methylbenzzyl) should be --(omethylbenzyl)--.

a a. Column 1?, the second formula N N N [COOH should be N COOH COOH COOH Column 1 4, the second formula,

N N g g L should be q (I: L O

SIGNED mi) SEALED JANZGWI E U Am Numb. lsumxmm. .m.

il-1:81am A .ngmfi 0 Pants 

